Neurofibromatosis type 1 (NF1) is a common (approximately 100,000 Americans) genetic disorder of dysregulated cell growth. Affected people can develop multiple (tens, hundreds, or thousands) of soft fleshy tumors called neurofibromas. People with NF1 also develop malignant cancers. There are limited therapies and no cures for NF1. At this time it is essentially impossible to predict the severity of the disorder. With few exceptions, neither mutation testing of the involved gene (NF1) nor the severity of other affected family members help in estimating the clinical course of the condition. In this study we study the wide variability in severity seen in families with NF1. In our translational approach in the protocol ?Variation in Gene Expression in Neurofibromatosis Type 1? we quantitatively evaluate families with NF1 using a variety of methods (physical exam, magnetic resonance imaging (MRI), skin and eye photography). We plan to correlate differences in these measurements with differences in the expression of genes, as determined by a microarray. The ultimate goal is to identify genes associated with severity. Differences in these genes (such as single nucleotide polymorphisms (SNPs)) may be useful in predicting the severity of the disorder. Gene products associated with severity may also be useful therapeutic targets.[unreadable] [unreadable] I joined NHGRI at the end of November 2004. The IRB approved the project in April 2005 and recruitment started shortly thereafter. By the end of fiscal 2006, we had phenotyped approximately 40 individuals affected with NF1 and collected DNA from nearly all their parents. A complementary project using large previously-banked NF1 pedigrees from Coriell Cell Repositories (Camden, NJ) and the European Collection of Cell Cultures (ECACC, Wiltshire, UK) is also underway. The purpose of this project is to determine the function of NF1 (the gene mutated in the disorder NF1) using a novel genetic and genomic method.[unreadable] [unreadable] In the past year we have also developed a collaborative project (using funds from the Bench-to-Bedside program) with Dr. Brigitte Widemann and Dr. Thomas Hornyak of the National Cancer Institute to investigate the growth and biology of neurofibromas. The project, titled ?Natural history and biology of dermal neurofibromas in neurofibromatosis type 1? was approved by the NHGRI IRB in May 2006. It is designed to investigate the growth rate and rate of appearance of dermal neurofibromas using several imaging modalities. We will also biopsy a dermal neurofibroma and normal skin. To streamline recruiting, the eligibility criteria overlap with that of our primary project, ?Variation in Gene Expression in Neurofibromatosis Type 1.? By the end of fiscal 2006, we had evaluated 5 individuals and had commitments to evaluate an additional 5 individuals.[unreadable] [unreadable] In fiscal 2005, we had accepted for publication in the Journal of Medical Genetics a paper on gastrointestinal stromal tumors (GISTs) in NF1 and had submitted for review a paper on the phenotype of pulmonary arterial hypertension in NF1. Also accepted for publication at the Journal of Clinical Endocrinology and Metabolism was a paper on the genetics of polycystic ovary syndrome (PCOS). This paper, done mostly as a post-doc at another institution, outlines many of the techniques in use on the current projects.